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Monday, July 28, 2025

Tadalafil


Generic name: Tadalafil
Drug class: Phosphodiesterase type 5 inhibitor (PDE5 inhibitor)
Formulation: Oral tablets
Available strengths: 2.5 mg, 5 mg, 10 mg, 20 mg
Route of administration: Oral
Primary indications:

  • Erectile dysfunction (ED)

  • Benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

  • Pulmonary arterial hypertension (PAH) (under different dosage and brand indication)

Tadalafil is a potent, long-acting PDE5 inhibitor that enhances blood flow to the penis by increasing intracellular cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum. Due to its prolonged half-life, tadalafil offers up to 36 hours of effectiveness, earning it the nickname “the weekend pill.” It also provides relief of LUTS in men with BPH and improves exercise capacity in PAH.

2. Mechanism of Action

Tadalafil selectively and reversibly inhibits phosphodiesterase type 5 (PDE5), the enzyme responsible for degrading cGMP in smooth muscle cells. Sexual stimulation leads to nitric oxide release, stimulating guanylate cyclase and raising cGMP within penile tissue. By inhibiting PDE5, tadalafil prolongs the vasodilatory effect of cGMP, facilitating erection.

In the prostate and lower urinary tract, increased cGMP mediates smooth muscle relaxation of bladder neck and prostatic tissue, improving urinary flow and reducing LUTS. In pulmonary vasculature, tadalafil relaxes pulmonary arteries, reducing pulmonary vascular resistance and improving exercise tolerance in PAH.

3. Pharmacokinetics

Absorption:

  • Rapidly absorbed after oral administration.

  • Peak plasma concentration achieved in approximately 2 hours (range 0.5–6 hours).

  • Food has minimal impact on absorption; can be taken with or without meals.

Distribution:

  • Volume of distribution ~63 L; moderately bound to plasma proteins (~94%).

Metabolism:

  • Metabolized extensively in the liver by cytochrome P450 3A4 (CYP3A4) to an active demethylated catechol metabolite.

Half-life:

  • Terminal half-life approximately 17.5 hours, enabling prolonged pharmacodynamic effects up to 36 hours.

Excretion:

  • Eliminated primarily via feces (~61%) and urine (~36%) as inactive metabolites.

4. Therapeutic Indications

4.1 Erectile Dysfunction (ED)

  • On‑demand dosing: 10 mg or 20 mg taken at least 30 minutes before anticipated sexual activity; maximum once daily.

  • Daily dosing option: 2.5 mg or 5 mg once daily, providing continuous treatment effect.

4.2 Benign Prostatic Hyperplasia (BPH) / LUTS

  • Daily dosing of 5 mg provides significant relief of urinary symptoms in men with BPH, even without ED.

  • May be combined with alpha-blockers or 5-alpha-reductase inhibitors depending on symptoms and prostate size.

4.3 Pulmonary Arterial Hypertension (PAH) (Brand-specific low dose)

  • Tadalafil 40 mg once daily improves exercise capacity and functional class in WHO class II–III PAH; different release form and dosage than ED/BPH use.

5. Dosage and Administration

Erectile Dysfunction – On-Demand Regimen

  • Initial dose: 10 mg orally prior to anticipated sexual activity.

  • Dose may be increased to 20 mg or reduced to 5 mg based on efficacy and tolerability.

  • Maximum frequency: once every 24 hours.

Erectile Dysfunction – Daily Regimen

  • 2.5 mg or 5 mg taken at approximately the same time each day.

  • Higher dose not recommended due to risk of adverse effects.

Benign Prostatic Hyperplasia / LUTS

  • 5 mg orally once daily, taken at the same time each day (with or without food).

  • In the presence of both ED and BPH, 5 mg or 10 mg on-demand or 5 mg daily may be appropriate, individualized per patient response.

PAH (Special Indication)

  • 40 mg once daily under supervision. Contraindications and warnings differ from ED/BPH use.

Special Administration Notes

  • Swallow tablets whole with water.

  • Avoid grapefruit and grapefruit juice (inhibits CYP3A4, potentially increasing tadalafil levels).

  • Missed dose in daily regimen should not be doubled; simply resume next scheduled dose.

6. Contraindications

  • Concurrent use of nitrates in any form (sublingual, buccal, transdermal, topical, or IV) due to risk of profound hypotension.

  • Known hypersensitivity to tadalafil or any component of the formulation.

  • Concomitant use of riociguat (in PAH context) or other nitric oxide donor drugs.

  • Unstable cardiovascular conditions such as recent myocardial infarction, uncontrolled arrhythmias, hypotension, or stroke within past 6 months.

7. Warnings and Precautions

  • Hypotension and syncope: especially when combined with alpha‑blockers or antihypertensives; caution during initiation.

  • Priapism: prolonged erection >4 hours requires emergency care to prevent permanent damage.

  • Vision changes: rare cases of non-arteritic anterior ischemic optic neuropathy (NAION) reported; caution in patients with risk factors (e.g., diabetes, hypertension, glaucoma).

  • Hearing loss: sudden decrease or loss reported rarely; discontinue if occurs.

  • Alpha-blocker co-administration: when given with selective alpha‑1 blockers (e.g. tamsulosin), initiate with low doses and monitor blood pressure.

  • Renal or hepatic impairment: dose adjustment may be required in severe impairment.

8. Adverse Effects

Common (≥1%)

  • Headache

  • Dyspepsia or indigestion

  • Back and muscle pain (typically transient and occurring 12–24 hours after dose)

  • Nasal congestion or rhinitis

  • Myalgia (muscle aches)

Less common (<1%)

  • Flushing or facial warmth

  • Dizziness or lightheadedness

  • Visual disturbances (blurred vision, color tinge)

  • Tinnitus or hearing abnormality

  • Palpitations

Rare but Serious

  • Non‑arteritic anterior ischemic optic neuropathy (NAION) resulting in vision loss

  • Severe hypotension or fainting

  • Priapism requiring medical attention

  • Hearing loss, sometimes sudden and bilateral

  • Severe allergic reactions, including angioedema or rash

9. Drug Interactions

  • Nitrates or nitric oxide donors: contraindicated; severe hypotension may result.

  • Alpha-blockers: additive hypotensive effects; initiate treatment carefully with close blood pressure monitoring.

  • CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin): increase tadalafil levels—dose reduction and monitoring advised.

  • CYP3A4 inducers (e.g. rifampin, carbamazepine): reduce tadalafil efficacy due to increased clearance.

  • PAH-specific drugs (e.g. riociguat): simultaneous use contraindicated due to risk of hypotension.

  • Antihypertensives: additive hypotension; monitor blood pressure when initiating or adjusting dose.

10. Use in Special Populations

Elderly

  • Pharmacokinetics generally not significantly altered; increased sensitivity to side effects may occur.

  • Start with the lowest effective dose (e.g. 5 mg daily or 5–10 mg on-demand).

Renal Impairment

  • Mild to moderate (CrCl >30 mL/min): no dose adjustment typically needed.

  • Severe renal impairment (CrCl <30 mL/min): reduce on-demand dose to 5 mg and avoid daily regimen.

Hepatic Impairment

  • Mild to moderate hepatic dysfunction: no adjustment required due to primary hepatic metabolism.

  • Severe hepatic dysfunction: use with caution; limit dose to 5 mg on-demand, with careful monitoring.

Pregnancy and Lactation

  • Not indicated in women; safety in pregnant or breastfeeding women not established.

Pediatrics

  • Not approved for use in children under 18 years.

11. Clinical Monitoring

  • Periodically assess erectile function response: ability to achieve and maintain erection, duration, frequency.

  • Evaluate urinary symptoms in BPH: flow rate, residual volume, frequency, nocturia, symptom score.

  • Monitor side effects such as headache, musculoskeletal discomfort, hypotension, vision or hearing changes.

  • Blood pressure monitoring when initiating or combining with antihypertensives or alpha-blockers.

  • Renal and hepatic function tests if impairment suspected or prolonged treatment used.

12. Overdose Management

Symptoms

  • Excessive hypotension

  • Visual disturbances

  • Priapism

  • Dizziness, nausea, palpitations

Management

  • Supportive care: ensure airway, breathing, and circulation stable.

  • Monitor vital signs and serve IV fluids if needed.

  • Stop tadalafil; no specific antidote exists.

  • Priapism longer than 4 hours requires urological evaluation to prevent ischemic damage.

13. Comparative and Clinical Considerations

  • Compared with other PDE5 inhibitors, tadalafil has the longest duration of action, allowing for spontaneous activity within a two‑day window after dosing.

  • Daily low-dose regimen offers continuous readiness for sexual activity and improves LUTS in men with BPH, offering convenience and symptom control without on‑demand dosing.

  • Tadalafil is particularly useful in men with both ED and BPH due to dual benefit.

  • Back and muscle pain are slightly more common with tadalafil than other PDE5 inhibitors due to sustained tissue exposure.

  • Lower risk of visual color‑tint effects (e.g. blue‑green) compared to sildenafil or vardenafil.

  • As an alternative for patients who prefer less planning around sexual activity, tadalafil daily or on-demand offers flexibility.

14. Patient Education Points

  • Sexual stimulation is required for an erection; tadalafil is not an aphrodisiac.

  • On-demand dosing: take 10 mg or 20 mg at least 30 minutes before planned activity; maximum once in 24 hours.

  • Daily dosing: take 2.5 mg or 5 mg at the same time each day, even if sexual activity is not daily.

  • Report any prolonged erection longer than 4 hours immediately.

  • Discontinue if sudden vision or hearing loss occurs and seek urgent evaluation.

  • Stand up slowly from sitting or lying positions to avoid dizziness—especially upon first dose or dose increase.

  • Inform your provider of all medications including nitrates, blood pressure drugs, or antifungals.

  • Do not use nitrate medications while on tadalafil; this combination can result in dangerous drops in blood pressure.



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